Management of Bone Sarcoma

a b c,d, Christina J. Gutowski, MD , Atrayee Basu-Mallick, MD , John A. Abraham, MD *

KEYWORDS Bone sarcoma Osteosarcoma Ewing sarcoma Chondrosarcoma Endoprosthetic reconstruction

KEY POINTS

Advancements in chemotherapy have been the primary reason for improvements in survival from bone sarcoma in the past 20 years. There are currently no chemotherapy agents effective against conventional chondrosarcoma. Local recurrence of bone sarcoma is likely related to aggressive tumor biology, but rela- tionship with survival is not fully understood. Multiple methods of reconstruction after bone sarcoma resection are available, each with its own benefits and drawbacks. Emerging technologies, such as computer-aided surgery, improved imaging, and improved implant design, have potential to improve results of treatment even further in the future.

INTRODUCTION Incidence and Epidemiology Bone sarcomas account for approximately 0.2% of new cancer cases in the United States each year. The vast majority of these are either osteosarcoma, Ewing sarcoma, or chondrosarcoma. In 2016, it is estimated that 3300 new cases will be diagnosed; this incidence has been rising on average 0.4% annually over the past decade.1 More than 27% of new diagnoses are made in patients younger than 20 years; osteosarcoma specifically is reported to be the third most common cancer in adolescence, and eighth

We have no funding sources, or commercial/financial conflicts of interest to disclose. a Department of Orthopedic Surgery, Sidney Kimmel Medical College at Thomas Jefferson Uni- versity, 1025 Walnut Street, Room 516 College, Philadelphia, PA 19107, USA; b Department of Medical Oncology, Sarcoma and Bone Tumor Center at Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, 1025 Walnut Street, Suite 700, Philadelphia, PA 19107; c Department of Orthopedic Surgery, Rothman Institute at Jefferson University Hospital, 925 Chestnut Street, Philadelphia, PA 19107, USA; d Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA * Corresponding author. E-mail address: [email protected]

most common cancer in children overall.2 Unlike osteosarcoma and Ewing sarcoma, which peak in adolescent age groups, chondrosarcoma incidence increases with age.3 It is estimated that 1490 patients will die of bone sarcoma in 2016, representing 0.3% of all cancer deaths.1 For osteosarcoma, the implementation of multimodal treatment with chemotherapy and surgery has led to a considerable improvement in overall survival, but since that time, survival rates have remained relatively stable. In 2015, cause-specific 10-year survival for patients with localized disease at the time of osteosarcoma diagnosis was 65.8%.4 Metastatic disease at presentation, which is seen in approximately 24% of patients, lowers this survival rate to 24%.4,5 Despite improvement in survival of localized disease with modern management, patients with recurrence or metastasis after initial treatment is still associated with a poor prognosis.

Pretreatment Evaluation and Staging The goal of the preoperative evaluation is to determine the extent of the disease, and allow for optimum treatment planning. Local imaging usually includes orthogonal plain radiographs and MRI of the affected area (Figs. 1 and 2). Computed tomography (CT) scan may be helpful in identifying cortical involvement. Imaging of the entire affected bone should be included to identify any skip metastases, the presence of which worsens prognosis.6 Evaluation of distant disease is done by using chest CT scan to evaluate for pulmonary metastasis, and Technicium-99 whole-body bone scan and/or PET with fludeox- yglucose F 18 (F18-FDG PET)/CT to evaluate for bony metastases7,8 (Fig. 3). Recent studies have demonstrated that PET/CT is more sensitive than bone scan for detect- ing metastatic bone lesions, while specificity and diagnostic accuracy were similar. The combination of bone scan and PET/CT provides the highest sensitivity, specificity, and diagnostic accuracy, but this must be balanced with the additional cost. PET/CT scan may have the additional benefit of demonstrating correlation with the aggressiveness of a bone lesion, although is not completely reliable for this purpose.9,10 Once biopsy is completed, various staging systems exist. The American Joint Com- mittee on Cancer (AJCC) is most commonly used. For bone sarcoma specifically, an alternative system frequently used is the Musculoskeletal Tumor Society (MSTS) system, described by Enneking in 198011 (Tables 1 and 2).

Biopsy When performed appropriately, diagnostic accuracy of surgical incisional biopsy has been shown to be 98%,12 and as such, surgical biopsy is the preferred method of

Fig. 1. Orthogonal radiographs and coronal short tau inversion recovery (STIR) MRI scan of conventional osteosarcoma of the right distal femur. Management of Bone Sarcoma 1079

Fig. 2. Anteroposterior radiograph and coronal STIR MRI scan of chondrosarcoma of the left proximal femur. obtaining tissue by most surgical pathologists. However, from a technical standpoint, open biopsy is associated with a complication rate of 16% and therefore must be performed by an experienced center. Mankin and colleagues13,14 demonstrated that biopsy-related problems occurred with 3 to 5 times greater frequency at centers inex- perienced with sarcoma treatment, when compared with sarcoma treatment centers. Several principles to minimize risk of contamination and complication while maintain- ing adequate yield and accuracy have been described (Box 1). Currently, percutaneous needle biopsy has replaced open surgical biopsy in most experienced centers as the primary method of biopsy due to low complication rate and a high level

Fig. 3. Technicium-99 whole-body bone scan of patient with localized osteosarcoma of the right distal femur. 1080 Gutowski et al

Table 1 American Joint Committee on Cancer staging system for bone sarcomas

Stage Tumor Size Lymph Involvement Grade IA <8 cm No lymph node involvement or metastasis Low IB 8 cm No lymph node involvement or metastasis Low IIA <8 cm No lymph node involvement or metastasis High IIB >8 cm No lymph node involvement or metastasis High III Skip metastasis No lymph node involvement or metastasis Any IVA Any size No lymph node involvement, metastasis to the lung Any IVB Any size Any lymph node involvement or any metastasis to site Any other than the lung

Adapted from Edge SB, Byrd DR, Compton CC, eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer, 2010.

of accuracy, but relies heavily on the acumen of the bone pathologist given the low yield of tissue from this procedure.

Percutaneous needle biopsy With complication rates of approximately 1%, percutaneous needle biopsy with or without image guidance represents a safe, cost-effective, minimally invasive alternative to surgical biopsy.16–19 Diagnostic accuracy rates range from 74% to 93% when imaging modalities are used.19–21 Major disadvantages of needle biopsies, in general, relate to the small amount of tissue obtained, and the potential for sampling error. For these reasons, fine needle aspirate (FNA) is usually insufficient for primary bone sarcoma. However, core needle biopsy (CNB) has consistently been shown to facilitate accurate histopathologic interpretation and achieve favorable patient outcomes.17,19,22 The difference in hospital charges associated with percutaneous biopsies and open biopsies was found to be approximately $6000.23 Furthermore, recent data suggest that seeding of the needle biopsy tract may not occur as it does in open surgical biopsy.24 Many studies have attempted to identify risk factors for poor diagnostic capability or patient outcome after CNB. Increased sensitivity, diagnostic accuracy, and ability to differentiate between benign and malignant lesions are seen in needle biopsy of bone sarcomas compared with soft tissue sarcomas.17,21,23 In general, malignant bone tumors are associated with higher diagnostic yield than benign lesions.24,25 Biopsies of necrotic areas of a tumor are likely to produce nondiagnostic tissue, so image guidance is critical in determining the optimal target of the biopsy needle. Highly

Table 2 Musculoskeletal Tumor Society staging system for bone sarcomas

Stage Grade Site IA Low Intracompartmental IB Low Extracompartmental IIA High Intracompartmental IIB High Extracompartmental III Any regional/distal metastases Any

From Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 1980;153:106–20. Management of Bone Sarcoma 1081

Box 1 Principles of safe and effective surgical biopsy of musculoskeletal lesions

Principles of surgical biopsy Plan the biopsy as carefully as the definitive resection procedure Carry out procedure with minimal contamination of normal tissues Drain tract must be clearly marked and close to and in line with surgical biopsy incision, to be resected at definitive procedure Pay careful attention to antiseptic technique, skin sterilization, hemostasis, and wound closure Avoid transverse incisions, and place skin incision in such a matter so as to not compromise subsequent definitive surgery Ensure adequate amount of representative tissue is obtained, communicate confirmation with pathologist Details must be provided to pathologist, including site of tumor, age, and radiologic differential diagnosis If pathologist is unable to make diagnosis, urge him or her to seek consultation promptly If the orthopedist or institution is not equipped to perform appropriate diagnostic studies, the definitive surgical resection, or adjuvant treatment, the patient should be referred to a treating center before biopsy performance Core needle biopsies under imaging control are often appropriate alternatives to surgical biopsy

Data from Refs.13–15

vascularized tumors risk excessive blood in the core sample. In each case, the treatment team should weigh the advantages and disadvantages of open versus percutaneous biopsy; while using a core needle has many advantages and is proven safe and accurate, in certain circumstances the appropriate course remains an open surgical biopsy. Although image guidance is usually by CT or ultrasound, MRI is becoming more readily available as a guidance modality for needle biopsy. In one large study, MRI- guided biopsy of bone lesions achieved 92% diagnostic sensitivity, 100% specificity, 100% positive predictive value, and 86% negative predictive value.26 MRI detects areas of highest yield better than other modalities, allowing for optimal needle placement without ionizing radiation exposure. Disadvantages of MRI-guided needle biopsy are cost, need for MRI-compatible biopsy needles, and patient-specific con- traindications to MRI, such as pacemakers, aneurysmal clips, or cochlear implants.27 For palpable lesions not in close proximity to neurovascular structures, office biopsy procedures have proven clinically effective, safe, and cost-efficient.28 No differences have been found in accuracy of specific diagnosis, malignancy status, grade, or histologic type between biopsy samples obtained by surgical procedure or percutane- ously without image assistance in the clinic setting for appropriate tumors.29

Treatment Overview A multidisciplinary sarcoma team consisting of an orthopedic oncologic surgeon, medical oncologist, radiation oncologist, bone pathologist, and musculoskeletal radi- ologist is critical in optimizing outcomes in the treatment of bone sarcoma. Overall treatment strategy should depend on a multitude of factors (Box 2). A hierarchy of 1082 Gutowski et al

Box 2 Criteria in surgical decision-making

Patient factors Patient age Personal/family/cultural considerations Oncologic factors Cancer stage Anatomic location Histologic subtype Histologic grade Treatment factors Response to induction chemotherapy Capabilities/biases of surgical team

Data from DeVita VT, Lawrence TS, Rosenberg SA. Cancer. Principles and practices of oncology. 10th edition. Philadelphia: Wolters Kluwer Health; 2015.

priorities exists when caring for a patient with sarcoma of bone: life, limb, limb function, limb length equality, and cosmesis (in that order).30 Local control is generally achieved with surgical resection, and for histologies in which chemotherapy is appropriate, systemic control is achieved with chemotherapy. A shift away from amputation in favor of limb salvage surgery has been observed, in an attempt to improve limb function without sacrifice of long-term survival.31–33 In the vast majority of extremity bone sarcoma, limb salvage can be performed. In some cases, radiation therapy can be used for local control in Ewing sarcoma. Aside from Ewing sarcoma, however, radiation therapy alone is not adequate for local control of bone sarcoma.34–36 After the primary tumor has been addressed, resection of all metastatic lesions that are technically feasible is recommended for osteosarcoma. Long-term survival has been shown to increase fivefold with complete resection of the primary tumor as well as the metastatic sites, compared with primary tumor resection alone.37 Survival can be as high as 75% in patients with a solitary lung metastasis that is resected along with the primary tumor, demonstrating the benefit of surgical treatment of all lesions when possible.38 For Ewing sarcoma and chondrosarcoma, metastasectomy may have similar benefit.39,40

TREATMENT MODALITIES Chemotherapy Before the 1970s, before the emergence of chemotherapy, more than 80% of patients diagnosed with osteosarcoma or Ewing sarcoma developed distant metastases and eventually died, even with adequate surgical treatment. Several large, randomized prospective trials have since demonstrated dramatic improvements in prognosis secondary to chemotherapeutics: Eilber and colleagues41 showed a 17% rate of relapse- free survival at 2 years for patients with nonmetastatic osteosarcoma treated without chemotherapy, compared with a 66% rate in similar patients treated with chemotherapy. These data illustrate the value of systemic therapy in conjunction with local control with the intent to reduce rate of future distant relapse. Management of Bone Sarcoma 1083

Although this is true for most aggressive tumors like conventional osteosarcoma and Ewing sarcoma, there is still no effective chemotherapy for certain bone tumors like chondrosarcoma. These rare tumors with complex management are generally treated in tertiary sarcoma centers in the context of a clinical trial or through well- established individualized treatment protocol based on multidisciplinary evaluation. In general, nonmetastatic high-grade osteosarcoma, Ewing sarcoma, and spindle cell sarcoma of bone are treated with neoadjuvant chemotherapy followed by definitive local therapy and then adjuvant chemotherapy.15

Chemotherapy for osteosarcoma The Multi-Institutional Osteosarcoma Study (MIOS) established the value that chemotherapy contributes to the treatment of high-grade osteosarcoma. Patients with newly diagnosed localized osteosarcoma of the extremity were randomized to resection followed by observation or followed by adjuvant chemotherapy. Sixty-six percent of the chemotherapy group were relapse-free compared with only 17% in the observation group at 2-year follow-up.42,43 Eilber and colleagues41 demonstrated similar findings, discontinuing their prospective randomized trial after 2 years due to the dramatically improved outcomes in the adjuvant chemotherapy group (55% vs 20% disease-free survival, and 80% vs 48% in improved patient survival). A similarly designed study explored the role of neoadjuvant chemotherapy in osteosarcoma with the POG-8651 trial. Patients were prospectively randomized to immediate surgery followed by 42 weeks of adjuvant chemotherapy, or 10 weeks of neoadjuvant chemotherapy followed by surgery then 32 weeks of adjuvant chemotherapy. The timing of surgery did not impact outcomes, as both cohorts fared equally well. With these results, the utilization of neoadjuvant chemotherapy became more widespread, as it allows for more time for surgical planning and for the assessment of histologic necrosis in response to neoadjuvant treatment.41 It also attempts to treat detectable metastases or presumed micrometastases as quickly as possible, and may also decrease the size of the primary tumor as well as promote tumor demarcation from surrounding tissues by decreasing neovascu- larity.44 It is estimated that approximately half of patients with localized disease display greater than 90% response to preoperative chemotherapy.45 In these responders, 5-year survival rates are more than 60%. For poor responders, this rate drops to 37% to 52%.46 The consensus standard chemotherapy regimen for high-grade osteosarcoma has become high-dose methotrexate, cisplatin, and doxorubicin. However, the type of chemotherapy should be based on age, comorbidities, tumor type and stage, and treatment expectations, with an understanding of the toxicities associated with various agents.47 Combining multiple drugs avoids chemoresistance and increases necrosis rate.48 In poor responders to the 3-drug regimen, the addition of ifosfamide to the postoperative regimen can lead to improvement in outcomes and cellular response similar to that of a good initial responder.49 Interestingly, though, trials adding ifosfamide to the neoadjuvant chemotherapy regimen from treatment onset did not improve overall survival or event-free survival50; for this reason, it is not consistently included in the traditional regimen for classic osteosarcoma. Moreover, results from EURAMOS trial presented in the 2014 October Connective Tissue Oncology Society meeting showed that adding ifosfamide and etoposide to poor responders does not improve overall survival.51 The optimal chemotherapy regimen for adults with osteosarcoma have not been determined, as most trials included patients younger than 40 years. However, in one trial that had patients up to 65 years of age there was no clear benefit seen 1084 Gutowski et al

from addition of high-dose methotrexate.52 Adults older than 40 years are generally treated with a doxorubicin and cisplatin-based treatment. Future directions in the systemic treatment of osteosarcoma involve target-selective chemotherapeutic drugs, such as mammalian target of rapamycin (MTOR) inhibitors, have shown activity in the metastatic setting.53 Additionally, liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) is being studied, which modifies the patient’s own immune system, stimulating the formation of tumoricidal macrophages. This agent has shown improved survivability in patients without clinically detectable metastases on presentation, through a mechanism unique to that of conventional chemotherapy.54

Chemotherapy for Ewing sarcoma Ewing sarcoma is the third most common primary malignant neoplasm of bone, with an annual incidence of 2.9 cases per million.55 It is more frequent in children and adolescents, and is the second most common bone malignancy in this age group.56 Median age at diagnosis is 15 years, but it is occasionally seen in adults. It is most common in whites and is very uncommon in African and Asian populations. Treatment for Ewing sarcoma is multimodal, involving chemotherapy for systemic control as well as either surgical resection or radiation therapy to achieve local control. Before introduction of multidrug chemotherapy protocols in the 1970s, 5-year survival for patients was less than 25%.57,58 Today, patients with localized disease experience 5-year survival rates that exceed 60%.59 Worse prognosis is associated with metastatic disease at presentation, tumor size greater than 10 cm, patient age 20 years or older, and axial tumor location.60 With isolated lung metastases on presentation, 5-year relapse-free survival is 29%. However, with bone metastases, this rate drops to 19%, and with metastases to both locations, the rate is 8%.61 One of the earliest clinical trials involving chemotherapy for Ewing sarcoma was the North American Intergroup Ewing Sarcoma Study (IESS-1), which showed success of a combination regimen abbreviated “VACA” or “VDCA”: vincristine, doxorubicin, actinomycin-D, and cyclophosphamide. It showed an improved 5-year relapse-free survival: 60% versus 24% versus 44% when compared with VAC (vincristine, Actinomycin-D, cyclophosphamide) or VAC with bilateral lung irradiation, respectively. It also showed that larger size and pelvic location tumors did worse.62 The optimal mode of VACA administration was clarified by the second Intergroup study, which demonstrated that early high-dose intermittent doxorubicin achieved better outcomes than the IESS-1 dose with relapse free survival in 5 years as high as 73% for nonpelvic tumors. It also showed better survival for large pelvic tumors compared with IESS-1.63 A further improvement in 5-year relapse-free survival was noted in nonmetastatic Ewing sarcoma with the addition of alternating ifosfamide and etoposide to the VDCA regimen versus VDCA alone (69% as opposed to 54%, respectively).64 Based on the previously described studies, the trend is to treat with 6-agent chemotherapy with 3 to 6 cycles upfront followed by local therapy followed by an additional 6 to 10 cycles of chemotherapy. High-dose chemotherapy with autologous stem cell transplantation for high-risk localized disease should be done only under a clinical trial at present times given lack of data for definite benefit.65 Given high response rates with alkylating agents that show a steep dose response curve dose intense regimens have been investigated; however, these have not shown to be clearly beneficial when compared with standard dosing and have increased toxicity.66 Another approach investigated was to give the same multidrug regimen every 2 weeks instead of every 3 weeks (ie, dose-dense). It was found to have similar toxicity Management of Bone Sarcoma 1085 as compared with the standard 3-week regimen; however, had a better event-free survival (73% vs 42%) in children.67,68 The benefit of a similar approach in adults seems to be unclear and appears to be limited to children younger than 17 years.69 Patients with the metastatic disease are treated with a similar approach to localized disease; however, they have a worse prognosis. High-dose chemotherapy followed by autologous hematopoietic transplantation has been studied in a nonrandomized setting and given mixed results from different trials; this approach is still considered investigational and should be done only under a clinical trial.70–72 The final results from Euro Ewing Trial will likely shed more light on the specific subset of patients who will benefit from this approach.73

Chemotherapy for chondrosarcoma Traditional chemotherapy plays a minimal role in the treatment of conventional chondrosarcoma.74,75 It may convey some benefit in select cases of dedifferentiated chondrosarcoma, but the literature to support this is controversial.76–79 However, exciting research into the molecular genetics of this disease may illuminate specific molecular targets to focus on. One effort is based on the genes coding for isocitrate dehydroge- nase (IDH-1 and IDH-2), as up to 70% of conventional chondrosarcomas carry a mu- tation at these gene loci. Animal models have demonstrated 50% to 60% growth inhibition of tumor cells after administration of a tool compound that overrides this pathologic IDH1/2 pathway.80 Another potential treatment involves many chondrosarcomas’ upregulation of hypoxia inducible factor-1 alpha (HIF1-a), which is associated with increased vascular endothelial growth factor (VEGF) production, increased cellular proliferation, and resistance to chemotherapy and radiation.81 Tyrosine kinase inhibitors target VEGF, and clear cell chondrosarcoma has shown good response to the tyrosine kinase inhibitor sunitinib in a case report.82 Approximately 96% of central conventional chondrosarcomas have mutations in the retinoblastoma (Rb) pathway, a well-known tumor suppressor gene.83 Trials are currently ongoing involving peme- trexed disodium, a multitargeted antifolate that prevents formation of precursor nucle- otides, thought to stop uncontrolled proliferation though interaction with the pathologic Rb mechanism.84,85 Last, MTOR inhibitors like sirolimus with cyclophosphamide have shown modest clinical activity in chondrosarcoma, making them another agent of interest for this mostly chemo-resistant disease.86

Radiation Therapy The role of radiation therapy in the treatment of primary localized bone sarcomas is limited. With the exception of Ewing sarcoma, radiation is not an effective standalone modality for local control. The use of radiation may be considered as an adjunct therapy in the case of a margin-positive resection, for palliation in the case of unresectable tumors, or for palliation in symptomatic primary tumors in the setting of widespread metastatic disease. In the setting of Ewing sarcoma, radiation alone has been shown to be an effective means of local control, although local recurrence rates are higher than with surgical resection. Radiation can be used in place of resection in cases of Ewing sarcoma when surgery would be associated with significant functional loss, such as in difficult locations of the pelvis, spine, or chest wall. A Children’s Oncology Group retrospective study of 465 patients with Ewing sarcoma treated with either surgery or radiation for local control, demonstrated similar event-free survival, overall survival, and distant failure rates on multivariate analysis comparing resection with radiation.87 The risk of local failure, however, was greater for the radiation group compared with the surgical resection group. This finding is corroborated by pooled analyses of the Cooperative 1086 Gutowski et al

Ewing Sarcoma Study (CESS) data, which found that patients who received definitive radiotherapy had lower event-free survival rates than surgical patients, whereas overall rate of distant failure did not differ.88,89 In 2006, Bacci and colleagues90 demonstrated that for appendicular Ewing sarcoma, surgery led to significantly improved 5-year event-free survival compared with radiation (68% vs 49%, respectively), whereas for patients with central tumors, which have higher rates of local recurrence at baseline, there was no significant difference found in event-free survival or local recurrence rates between those treated with radiation or surgery. Advanced radiotherapy techniques have been studied extensively in Ewing sarcoma, such as proton beam radiation,91 brachytherapy,92 and intraoperative radiation.93 In a 2012 report of initial results of 30 pediatric patients with Ewing sarcoma treated with proton beam therapy, Rombi and colleagues94 demonstrated the low toxicity profile of this technique with an 86% rate of local control for an average of 38.4 months. Overall survival was found to be 89%. Hoekstra and colleagues95 suggested a positive effect on local recurrence with intraoperative radiotherapy (IORT) in a pilot study on 5 patients with pelvic girdle sarcomas; 80% of patients remained locally free of tumor with follow-ups of 8 to 53 months, in comparison with the 27% rate observed in historic controls. In 2015, a 20-year follow-up study on 71 patients treated with intraoperative electron beam radiotherapy found a 74% 10-year local control, 57% disease-free survival rate, and 68% overall survival rate in patients undergoing intraoperative radiotherapy for Ewing sarcoma (37 patients) or rhabdomyo- sarcoma (34 patients), arguing in support of this technique as a well-tolerated strategy to improve local recurrence rates.93 A role for proton beam radiation in combination with surgery is being established in the treatment of chordoma, particularly localized to the skull base or axial skeleton. Data from a prospective study examining the outcome of proton therapy as either adjuvant or definitive treatment for nonmetastatic chordoma or chondrosarcoma demonstrated local recurrence-free survival of 92%, with disease-free survival of 87%.91 Longer-term studies have corroborated these findings, reporting local recurrence to be 7.8% at mean follow-up of 69.2 months, for a cohort of 77 patients with skull-base chondrosarcoma.96 Carbon ion beam radiotherapy, which delivers a larger mean energy per unit length of trajectory than photon or proton beams, has shown positive results in the treatment of certain bone sarcomas.97 This method has been studied primarily in unresectable bone tumors98 and in patients refusing surgery.99 A local recurrence rate of 62% and 5-year overall survival rate of 33% was demonstrated in a study of 78 patients with medically inoperable osteosarcoma of the trunk who received carbon ion beam radiotherapy.100 Results are more favorable in patients with medically unresectable sacral chordomas: Imai and colleagues101 reported an overall survival rate at 5 years of 86% in their 95-patient cohort, with local control rate at 5 years of 88%. In their more recent report, the same group observed 5-year and 10-year local control rates of 77.2% and 52%, respectively, in 188 cases of unresectable sacral chordomas after carbon ion therapy alone.98 This is comparable, if not favorable, to the accepted local recurrence rate after surgery being approximately 45% to 78%.102,103 Five-year and 10-year survival rates were 81.1% and 66.8%, respectively. Nishida and colleagues104 demonstrated that the functional outcomes reported after surgical resection were 55% according to the Musculoskeletal Tumor Society scoring system, whereas they were 75% after carbon ion beam radiotherapy, and that definitive radiation treatment was associated with significantly improved emotional acceptance scores. The most common complications of radiation therapy are wound complications, limb-length discrepancies, joint contractures, pathologic fractures, and secondary Management of Bone Sarcoma 1087 malignancy. Even relatively low doses have been associated with the development of radiation-induced sarcomas within the field,105 and there is evidence that radiation- associated soft tissue sarcomas carry a worse prognosis than those not related to radiation exposure.106 As the population of long-term cancer survivors grows, these long-term sequelae will become increasingly concerning, and must be reconciled with the improvements in oncologic outcomes associated with advanced radiotherapy techniques.107

Surgical Resection The primary goal of surgical treatment of bone sarcoma is to achieve complete resection of the primary tumor with negative margins, with a secondary goal being preservation of as functional a limb as is possible. Sarcoma growth has been described as “centrifugal,” or from the inside outward, and as tumor growth progresses, a pseudo- capsule develops at the interface of tumor and normal tissue. Pseudopods of tumor extend into this reactive zone; resection through this zone will leave tumor cells behind.11 Adequate resection is critical, as margin status is the most important deter- minant of recurrence.7,108,109 National Comprehensive Cancer Network guidelines recommend wide local excision of bone sarcomas7; however, “wide resection” is not easily defined (Table 3). In poor responders to preoperative chemotherapy, a wider margin may be needed to achieve a definitive resection.110 In the pelvis and spine, complete resection is often more challenging than it is in the extremities due to anatomic complexity.111,112 In a recent study of 52 patients with pelvic bone sarcomas, Farfalli and colleagues113 found that 15% of resections resulted in intralesional margins, 63% with marginal margins, and only 21% wide margins; intralesional resection was found to be a significant risk factor for local recurrence in this and other series. In a report of 1121 patients with extremity sarcomas, the same institution reported that only 9% of resections resulted in inadequate margins, highlighting the importance of anatomic location of the tumor when planning surgical resection.108

Resection: amputation versus limb salvage Before the popularization of limb salvage surgery (LSS) in the 1970s, amputation was the standard of care for malignant bone tumors. Improvements in chemotherapy protocols have been the primary advancement that supported a paradigm shift away from amputation and toward LSS for sarcoma of the extremities. Additional advancements in endoprosthetic design, musculoskeletal imaging, and surgical technique have all contributed to the success of LSS in most cases. With modern treatment, it is estimated that limb salvage surgery is a reasonable option in 85% of appendicular oste- osarcomas.114 In some cases, however, amputation still remains the best surgical option, most commonly in the setting of critical nerve involvement. No prospective randomized study exists comparing oncological outcomes of LSS with those after amputation. Nonrandomized comparative studies have shown no statistically significant difference in overall survival.32,115,116 In 2015, Reddy and

Table 3 Margins in surgical tumor resection

Type of Margin Plane of Dissection Intralesional Within diseased tissue of tumor Marginal Within reactive zone Wide Through normal tissue, beyond reactive zone Radical Extracompartmental 1088 Gutowski et al

colleagues117 reported that amputation in patients with osteosarcoma conferred no clear survival benefit over LSS, even in the subset of patients with close margins during LSS and poor response to neoadjuvant chemotherapy. Quality of life after amputation and LSS has been shown to be similar by many studies.118,119 In a recent survey of 250 patients who received amputation for pelvic/lower extremity tumors, 84% of patients who had undergone hemipelvectomy, hip disarticulation, or transfemoral amputation required use of a walking aid and reported significantly higher pain levels than those who did not. The average Toronto Extremity Salvage Score (TESS) in all responders in this study (all amputation levels: hemipelvectomy to foot) was 56.4%,120 as compared with the 85% TESS achieved by patients treated with LSS in a separate report.121 Up to 83% of patients treated with LSS for Ewing sarcoma were found to participate in sports on a regular basis.122 Physiologic cost index, a measure of energy consumption, was also found to be greater after above-knee amputation than LSS.121 Job satisfaction, occupational rela- tions, material well-being, and reintegration into normal daily living activity are higher among patients treated with LSS than those undergoing above-knee amputation.121,123 Financially, external prosthetic fitting costs for amputees have been shown to surpass the cost of limb salvage in the long term: most active young patients will require a sophisticated artificial limb that will be replaced many times, and will opt for a second prosthesis for sports and swimming.124 Although functional results may be better in some cases after limb salvage than amputation, complications unique to reconstruction occur 3 times more commonly after LSS, and 4 times more commonly after endoprosthetic reconstructions, compared with ablative procedures.125 Return to the operating room is more frequent in patients undergoing LSS compared with amputees.124 Complications after LSS have been clas- sified into “mechanical,” “nonmechanical,” and “pediatric” modes of failure.126 Soft tissue failure, aseptic loosening, and breakage/fracture/dislocation of the implant comprise the “mechanical failure” category. Infection and tumor progression are included in the “nonmechanical” category, and pediatric complications, such as growth arrest and joint dysplasia, comprise the third. In cases of amputation, the risk of many of these complications is nonexistent; instead, amputees most often suffer from wound breakdown, infection, and phantom limb pain. Rates of wound infection have been reported to be as high as 45% in patients undergoing hindquarter amputation,127 but are generally much lower when the amputation occurs more distally.119,125,128 Wound complication rates as high as 38%, and infection rates of 11%, have been reported after LSS.129,130 Risk factors for infection include pelvic reconstruction (with allograft or endoprosthesis), tibial endoprosthetic reconstruction, radiation therapy, and pediatric expandable implants.113,130,131 Most deep infections occur within the initial 2-year postoperative period, or within 2 years of the most recent surgical intervention. In a study of patients with infected endoprosthetic reconstructions, local surgical debridement with or without placement of antibiotic implants was successful only 6% of the time; 37% ultimately underwent amputation to treat their infection.130 In patients who underwent allograft reconstructions, greater risk of infection was associated with tibial allografts, male patients, procedures performed in a conventional operating room, and prolonged utilization of postoperative antibiotics. In 82% of cases of allograft infection, local debridement failed and removal with antibiotic cement spacer placement was required.132

Local recurrence Local recurrence after bone sarcoma resection remains incompletely understood. The literature is inconclusive on whether LSS in the era of chemotherapy is associated with Management of Bone Sarcoma 1089 an increased risk of local recurrence compared with amputation.108,116,133 Classically, a close link between margin status and local recurrence has been shown, and the emergence of LSS has been suggested to increase the incidence of inadequate margins.108 However, the definition of an adequate margin in this context is unknown. In a recent study, Li and colleagues134 examined the impact of a close margin (<5 mm) on local recurrence in patients with osteosarcoma receiving chemotherapy and found no increase in local recurrence rate compared with wider margins. A similar finding was obtained in a large analysis of 1355 patients with osteosarcoma receiving surgery and chemotherapy: although surgical margin width was not a risk factor for local recurrence, a poor response to neoadjuvant chemotherapy and an inability to complete the chemotherapy protocol were significantly associated with local recurrence.135 In an investigation of local recurrence of chondrosarcoma, a notably chemotherapy- insensitive tumor, amputation versus limb salvage was not found to be a significant risk factor for local recurrence; tumor size and margin status were.109 These data support the current prevailing concept that local recurrence is a function of tumor biology as well as margin status. The prognostic significance of local recurrence in the absence of distant metastases on overall survival is not fully understood.136–138 Local recurrence was found to be a significant and independent predictor of poor overall survival in chondrosarcoma, imparting a hazard ratio of 3.4 according to one study.109 Although distant osteosarcoma metastases confer a poor prognosis,139 one study showed 31% of those with local recurrence alone were cured by further treatment.140 Another study found 5-year postrecurrence survival in patients with osteosarcoma with local recurrence without distant metastasis to be 42%, and 58% of these patients eventually developed distant metastases despite local treatment of their relapse.141 In a recent case-control study, Kong and colleagues142 showed local recurrence to have very lit- tle impact on overall survival in patients with high-risk osteosarcoma; instead, initial tumor volume and enlargement after chemotherapy were significant predictors of poor survival. Through a multivariate analysis, they suggest that poor histologic response and enlargement after chemotherapy are drivers of both local recurrence and poor overall prognosis individually, and that these 2 outcomes are not themselves causally associated. Findings such as these introduce questions regarding surgical treatment for local recurrence; for example, is repeat limb-sparing surgery adequate? In their 2006 study of 44 patients, Bacci and colleagues143 found that amputation for local recurrence did confer a longer postrecurrence survival than a second limb- sparing procedure. In 2014, Loh and colleagues144 reported that in 18 pediatric patients with locally recurring osteosarcoma in the absence of metastases at time of relapse, postrecurrence survival was significantly longer in patients in whom surgical margins of more than 1 cm were achieved during resection of the local recurrence. Takeuchi and colleagues141 reviewed 45 patients with localized recurrence of high- grade osteosarcoma and found that independent predictors of worse overall survival were recurrent tumor size greater than 5 cm and concurrent metastasis. The relation- ship between local recurrence and survival is therefore complex, and is likely a function of both adequacy of surgery and aggressiveness of the tumor.

RECONSTRUCTIVE CONSIDERATIONS Resection of tumors in “expendable bones,” such as the fibula, patella, scapula, or radius/ulna, is often successful without reconstruction. In other weight-bearing locations, structural integrity must be restored through reconstruction to optimize postoperative function. Options for reconstruction include allograft, allograft-prosthetic 1090 Gutowski et al

composite, endoprosthesis, and extracorporeal irradiated autograft. Emerging technologies promise future improvements in implant design, fixation and function, oper- ative technique, and mitigation of complications.

Allograft Reconstruction Advantages of this allograft reconstruction include restoration of bone stock, potential sparing of uninvolved adjacent joints in intercalary reconstructions, and anatomic soft tissue attachment sites.145 Disadvantages include the requirement for weight-bearing protection until allograft-host healing, potential for osteoarthritis development (in osteoarticular grafts), risk of disease transmission or graft rejection, and risk of oper- ative complications of allografts: nonunion, fracture, and infection.145,146 Up to 20% of initial allograft reconstructions fail, and up to 54% of patients may have a complication that requires additional surgery.147–149 Success rates vary with type of graft reconstruction used. Intercalary allografts have been associated with acceptable long-term functional outcomes in 82% to 84% of patients,150,151 and limb survival as high as 97%.149 Osteoarticular allografts have shown slightly worse success rates (61% and 63% good or excellent results at long-term follow-up, respectively, according to one study of femoral reconstruction).145 In a recent report of 87 patients who underwent intercalary allograft reconstruction with at least 24 months of follow-up, Bus and colleagues146 reported that up to 76% of their patients experienced 1 or more complications, most often nonunion (40%). Risk factors for failure and complications included age of 18 years or older, allograft length greater than or equal to 15 cm, intramedullary nail-only fixation, and diaphyseal localization, and these findings were consistent with those previously reported.150,152 There is general consensus regarding age, length, lack of rigid fixation, and diaphyseal location as risk factors for complications after this procedure. Graft fracture and nonunion are thought to possibly result from the avascular nature of the bulk allograft.153,154 To address this challenge, the implantation of massive allograft encasing an intercalary vascularized fibula autograft was described in the literature in 1993, and has come to be known as the “Capanna technique.”155 In the 2007 report of their long-term results, Capanna and colleagues156 reported a significant improvement in fracture risk: 13% in their series compared with baseline allograft fracture rates in of 17% to 34%; and nonunion rate of 8.8% in their series compared with the 12% to 63% rate established in the literature on allografts alone. Their overall success rate was reported as 93.5%, with 73.0% of their patients healing after the first operation and not requiring additional surgery, and this is in contrast to the large subset of patients treated with allograft who require a second procedure.151 In their 2016 study of 18 pediatric/adolescent patients undergoing the Capanna technique, Houdek and colleagues154 were unable to recreate the initially reported results; a 33% nonunion rate and 39% allograft fracture rate were observed. Although this technique is technically challenging and time-consuming, it may represent a step toward improvement in outcome of allograft reconstruction that can be achieved as our understanding of the technique’s failure mechanisms continues to advance.

Allograft-Prosthetic Composites One of the challenges of using osteoarticular allografts for joint reconstruction is the inability to adequately cryopreserve chondrocytes in the graft. This, combined with the instability that often occurs after suboptimal graft fixation, leads to accelerated cartilage degeneration.157,158 Allograft-prosthetic composite (APC) reconstructions (Figs. 4 and 5) offer the durability of a prosthetic articular surface reconstruction, combined with the enhanced soft tissue attachment capability of an allograft.159 APC Management of Bone Sarcoma 1091 reconstructions have been found to provide better stability in certain anatomic locations for an arthroplasty component than a stemmed endoprosthetic implant, poten- tially due to enhancement of soft tissue attachment sites.160,161 Once healing has occurred between the graft and host bone, the stress transfer from the implant to the host bone resembles that of a standard arthroplasty as compared with the stress concentration at the stem-body junction that occurs with megaprostheses.159 The technique is most often used in lower extremity joints162 but has also been described in conjunction with reverse total shoulder arthroplasty with good results.163 Weight-bearing restriction is still required postoperatively to allow for allograft incor- poration, which is delayed by chemotherapy. Nonunion is the most common complication facing this procedure, reported at nearly 23% in one study.164

Endoprosthetic Reconstruction Endoprosthetic replacement is the most common method of limb salvage reconstruction after bone tumor resection in the adult population.165 This strategy provides near- immediate stability of the limb and allows for earlier weight bearing than biologic reconstructive options, and the technology involved has advanced considerably over recent years. In 1993, one report showed event-free prosthetic survival at 5 years to be 88% for the proximal femur, 59% for the distal femur, and only 54% for the proximal tibia.166 More recently, 5-year implant survival has been reported to have improved to as high as 78.0% for lower extremity and 89.7% for upper extremity reconstructions.33,167 A 2016 report of distal femoral endoprosthetic reconstruction showed a 93% rate of limb salvage over a 25-year period at one institution.168 Revision rates, however, are high, with one study reporting a 34% overall revision rate at an average of 15 years of follow-up, due to mechanical failure (15%), infection (10%), and local disease recurrence (5%).169 In 2006, Farid and colleagues160 published a head-to-head comparison of endoprosthetic and APC reconstruction of the proximal femur. They found similar rates of complications in both groups: in the endoprosthetic group, the most common

Fig. 4. Left proximal humerus reconstruction with allograft-prosthetic composite reverse total shoulder arthroplasty. 1092 Gutowski et al

Fig. 5. Right proximal tibia reconstruction with allograft-prosthetic composite hinged total knee arthroplasty.

adverse outcome was aseptic loosening, which occurred 10% of the time. In the APC group, a 10% rate of graft nonunion was encountered. Musculoskeletal Tumor Society scores were similar for both groups, as was implant survivorship at 10 years. The greatest difference found was that the patients with APC regained significantly greater hip abductor strength, which may have imparted improved ambulatory function. Regarding distal femur resections, AlGeshyan and colleagues170 compared gait parameters in patients undergoing allograft reconstruction versus metallic endoprosthetic reconstruction. They found that although all patients exhibited decreased range of motion at the knee postoperatively, the allograft-reconstructed knees demonstrated normal patterns of rotation, whereas the patients with endoprosthetic reconstruction had abnormal patterns of rotation and differences in rotational mo- ments. A study conducted by Benedetti and colleagues171 found significant decrease in knee extension strength after metallic distal femoral replacement. They also observed a stiff-knee gait pattern in their patients who required much of the vastus medialis and intermedius to be resected before endoprosthetic reconstruction. These data suggest that although massive endoprosthetic replacement is the most popular reconstructive option, recreation of normal joint kinematics and optimization of soft tissue reattachment to these metal implants remains a challenge.

Extracorporeal-Irradiated Autografts Extracorporeal irradiation of a bone tumor resection specimen, followed by reimplantation of the autograft bone was first described by Spira and Lubin in 1968.172 This technique facilitates reconstruction of defects with an inexpensive, anatomically identical graft that restores bone stock, and obviates the risk of disease transmission and graft rejection.173,174 Puri and colleagues174 described optimization of the technique in 2012, beginning with transverse osteotomies at either end of the resection segment after indicator marks are created to facilitate rotational alignment at reimplantation.175 Soft tissue and periosteum are then sterilely stripped from the bone, before the bone is wrapped in vancomycin-soaked gauze for transport from the operating room. A single 50-Gy dose of radiation is administered to the resected segment using 6-MV photons or 60 cobalt gamma rays with parallel opposing portals. The marrow contents are reamed out and bone cement is injected into the medullary cavity, and then the specimen is reimplanted in appropriate rotational alignment and secured with internal Management of Bone Sarcoma 1093 fixation. In a report of 31 patients, the osteotomy sites united primarily in 88% of cases. This rate is higher than most union rates reported after cadaveric allograft fixation,151 and may be due to the precise geometric matching of the osteotomized ends. A 13.0% infection rate and 9.6% local recurrence rate were observed; all recurrences were associated with disseminated disease in the soft tissue, noncontiguous with the irradiated graft. Other studies have shown the rate of fracture for irradiated grafts to be as high as 20%.173,176 Use of a vascularized fibula autograft in conjunction with the irradiated host autograft bone has been described, associated with 88% good or excellent functional outcome.177

Emerging Surgical and Implant Technology As the number of young, active sarcoma survivors continues to rise, it is expected that rates of aseptic mechanical loosening will rise in parallel.178 One implant strategy to combat this is an alternative implant fixation device, the Compress prosthesis, which is designed to apply compression at the bone-implant interface, resulting in hypertro- phic bone growth in accordance with the Wolff law179 (Fig. 6). This relatively new device has a published survival rate as high as 89% at 5 years and 80% at 10 years when used for primary oncologic reconstruction,180–182 and comparison studies have shown it to achieve equal or higher survival rates than cemented and press-fit stemmed implants.183,184 The device may have a role in the revision settings as well, after endoprosthetic failure with standard stem fixation has occurred. Radiolucent intramedullary nails made of carbon fiber–reinforced polyetheretherke- tone (CFR-PEEK) as an alternative to metal implants have recently been shown to minimize implant artifact on MRI or CT in patients who underwent long-bone fixation requiring postoperative cross-sectional imaging surveillance. In comparison with titanium nails, a statistically significant superiority of the percentage of visualized cortex, corticomedullary junction, and muscle-bone interface on MRI images of CFR-PEEK nails was observed, which suggests potential benefit of this material in the setting of oncologic reconstructions.185 Additionally, biomechanical testing has found the 4-point bending strength, torsional stiffness, and bending fatigue of these implants to be comparable to titanium nails, with an inert biochemical profile and similar elastic modulus to bone.186 The CFR-PEEK nail was not associated with increased risk of su- perficial or deep infection, painful or symptomatic hardware, or completion of an impending pathologic fracture.

Computer-Aided Surgery Navigation technology has been used in orthopedic spine surgery, trauma surgery, and arthroplasty for many years, and has been shown to improve the precision and reproducibility of hardware placement.187–189 In orthopedic oncology, initial reports of intraoperative navigation focused on the safety and improved visualization achieved during pelvic mass excision.190 Over time, additional advantages of computer-aided surgery beyond surgical navigation alone have been realized that are applicable to the resection and reconstruction of bone sarcoma. In a simulation study by Cartiaux and colleagues,191 it was found that experienced surgeons achieved negative margins only 52% of the time when performing complex musculoskeletal resections on plastic models; the addition of computer-aided surgery to these simulations improved negative margin achievement significantly. In vivo, these findings have been supported by studies that have shown the intralesional resection rate of pelvic tumors improving from 29.0% to 8.7%, with addition of computer-aided surgery to traditional resection techniques,192 and accuracy of pelvic/sacral tumor resection within an average of 2.82 mm of planned osteotomies 1094 Gutowski et al

Fig. 6. (A) Preoperative STIR coronal MRI scan of right femur diaphyseal undifferentiated pleomorphic sarcoma of bone. (B, C) Intercalary prosthetic reconstruction with Compress device after resection. Management of Bone Sarcoma 1095 when performed with navigation.193 Cho and colleagues194 suggested a decrease in local recurrence rates as a result of improved margin status. For resection of bone sarcomas in anatomically challenging areas such as the pelvis, sacrum, or spine, the ability of navigation to preoperatively map a tumor’s extent and couple it to enhanced 3-dimensional intraoperative visualization offers great promise. In the case of epiphyseal or metaphyseal long-bone sarcomas, computer-aided surgery allows for precise periarticular resection that can be used to preserve the whole or partial epiphysis.195 The improvement in precision of hardware placement using computer-aided surgery has been shown in the trauma and spine literature, particularly with the placement of dangerous screws across the sacroiliac joint, acetabular region, and pedi- cles.196–198 In oncology applications, computer-aided design and computer-aided modeling cutting jigs, patient-specific instrumentation, and a custom-designed pros- theses can achieve accurate and precise reconstruction of a large bony defect in addition to aiding with hardware placement.199 Advanced preoperative planning using computer-aided surgical techniques can allow 2 surgical teams to work simulta- neously, one performing the resection and the other creating an allograft identical to the resection specimen to be used for reconstruction.200 A similar technique can be applied to custom-made metallic implants, in which the implant manufacturer and surgeon work on the same preoperative plan to create an implant that precisely matches the resection.

SUMMARY Treatment of bone sarcoma requires careful planning and involvement of an experienced multidisciplinary team. Significant advancements in systemic therapy, radiation, and surgery in recent years have contributed to improved functional and survival outcomes for patients with these difficult tumors, and emerging technologies hold promise for further advancement.

REFERENCES 1. SEER Stat Fact Sheet: Bone and Joint Cancer. National Institutes of Health Sur- veillance, Epidemiology, and End Results Program. Available at: http://seer. cancer.gov/statfacts/html/bones.html. Accessed February 16, 2016. 2. Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res 2010;152:3–13. 3. Arora RS, Alston RD, Eden TOB, et al. The contrasting age-incidence patterns of bone tumours in teenagers and young adults: implications for aetiology. Int J Cancer 2012;131(7):1678–85. 4. Duchman KR, Gao Y, Miller BJ. Prognostic factors for survival in patients with high-grade osteosarcoma using the Surveillance, Epidemiology, and End Re- sults (SEER) Program database. Cancer Epidemiol 2015;39(4):593–9. 5. Jawad MU, Cheung MC, Clarke J, et al. Osteosarcoma: improvement in survival limited to high-grade patients only. J Cancer Res Clin Oncol 2011;137:597–607. 6. Sajadi KR, Heck RK, Neel MD, et al. The incidence and prognosis of osteosarcoma skip metastases. Clin Orthop Relat Res 2004;426:92–6. 7. American Joint Committee on Cancer: Bone. In: Edge SB, Byrd DR, Compton CC, et al, editors. AJCC Staging Manual. ed 7. New York: Springer; 2010. p. 281–90. 8. Meyer JS, Nadel HR, Marina N, et al. Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children’s Oncology Group Bone Tumor Committee. Pediatr Blood Cancer 2008;51(2):163. 1096 Gutowski et al

9. Costelloe CM, Chuang HH, Madewell JE. FDG PET/CT of primary bone tumors. Am J Roentgenol 2014;202:W521–31. 10. Dimitrakopoulou-Strauss A, Strauss LG, Heichel T, et al. The role of quantitative F18-FDG PET studies for the differentiation of malignant and benign bone lesions. J Nucl Med 2002;43:510–8. 11. Enneking WF, Spanier SS, Goodman MA. A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 1980;153:106–20. 12. deHeeten GJ, Oldhoff J, Oosterhuis JW, et al. Biopsy of bone tumours. J Surg Oncol 1985;28(4):247–51. 13. Mankin HJ, Lange TA, Spanier SS. The hazards of biopsy in patients with malignant primary bone and soft-tissue tumors. J Bone Joint Surg Am 1982;64-A(8): 1121–7. 14. Mankin HJ, Mankin CJ, Simon MA. The hazards of biopsy, revisited. For the members of the Musculoskeletal Tumor Society. J Bone Joint Surg Am 1996; 78-A(5):656–63. 15. European Sarcoma Network Working Group. Bone sarcomas: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol 2012; 23(S7):vii100–9. 16. Dupuy DE, Rosenberg AE, Punyaratabandhu T, et al. Accuracy of CT-guided needle biopsy of musculoskeletal neoplasms. Am J Roentgenol 1998;171(3): 759–62. 17. Pohlig F, Kirchhoff C, Lenze U, et al. Percutaneous core needle biopsy versus open biopsy in diagnostics of bone and soft tissue sarcoma: a retrospective study. Eur J Med Res 2012;17:29. 18. Ogilvie CM, Torbert JT, Finstein JL, et al. Clinical utility of percutaneous biopsies of musculoskeletal tumors. Clin Orthop Relat Res 2006;450:95–100. 19. Welker JA, Henshaw RM, Jelinek J, et al. The percutaneous needle biopsy is safe and recommended in the diagnosis of musculoskeletal masses. Cancer 2000;89(12):2677–86. 20. Hau A, Kim I, Kattapuram S, et al. Accuracy of CT-guided biopsies in 359 patients with musculoskeletal lesions. Skeletal Radiol 2002;31(6):349–53. 21. Kiatisevi P, Thanakit V, Sukunthanak B, et al. Computed tomography-guided core needle biopsy versus incisional biopsy in diagnosing musculoskeletal lesions. Skeletal Radiol 2002;31(6):349–53. 22. Mitsuyoshi G, Naito N, Kawai A, et al. Accurate diagnosis of musculoskeletal lesions by core needle biopsy. J Surg Oncol 2006;94(1):21–7. 23. Skrzynski MC, Biermann S, Montag A, et al. Diagnostic accuracy and charge- savings of outpatient core needle biopsy compared with open biopsy of musculoskeletal tumors. J Bone Joint Surg Am 1996;78A(5):644–9. 24. UyBico SJ, Motamedia K, Omura MC, et al. Relevance of compartmental anatomic guidelines for biopsy of musculoskeletal tumors. J Vasc Interv Radiol 2012 Apr;23(4):511–8. 25. Didolkar MM, Anderson ME, Hochman MG, et al. Image guided core needle biopsy of musculoskeletal lesions: are nondiagnostic results clinically useful? Clin Orthop Relat Res 2013;471:3601–9. 26. Carrino JA, Khurana B, Ready JE, et al. Magnetic resonance imaging-guided percutaneous biopsy of musculoskeletal lesions. J Bone Joint Surg Am 2007; 89:2179–87. 27. Alanen J, Keski-Nisula L, Blanco-Sequeiros R, et al. Cost comparison analysis of low-field (0.23T) MRI- and CT-guided bone biopsies. Eur Radiol 2004;14(1): 123–8. Management of Bone Sarcoma 1097

28. Adams SC, Potter BK, Pitcher DJ, et al. Office-based core needle biopsy of bone and soft tissue malignancies. Clin Orthop Relat Res 2010;468:2774–80. 29. Srisawat P, Verraphun P, Punyaratabandhu T, et al. Comparative study of diagnostic accuracy between office-based closed needle biopsy and open incisional biopsy in patients with musculoskeletal sarcomas. J Med Assoc Thai 2014;97(S-2):S30–8. 30. DeVita VT, Lawrence TS, Rosenberg SA. Cancer. Principles and practices of oncology. 10th edition. Philadelphia: Wolters Kluwer Health; 2015. 31. Rosen G, Murphy ML, Huvos AG, et al. Chemotherapy, en bloc resection, and prosthetic bone replacement in the treatment of osteogenic sarcoma. Cancer 1976;37:1–11. 32. Eillber FR, Eckhardt J, Morton DL. Advance in the treatment of sarcomas of the extremity: current status of limb salvage surgery. Cancer 1984;54:2695–701. 33. Goshenger G, Gebert C, Ahrens H, et al. Endoprosthetic reconstruction in 250 patients with sarcoma. Clin Orthop Relat Res 2006;450:164–71. 34. Schwarz R, Bruland O, Cassoni A, et al. The role of radiotherapy in osteosarcoma. Cancer Treat Res 2009;152:147–64. 35. Errani C, Longhi A, Rossi G, et al. Palliative therapy for osteosarcoma. Expert Rev Anticancer Ther 2011;11:217–27. 36. Mahajan A, Woo SY, Kornguth DG, et al. Multimodality treatment of osteosarcoma: radiation in a high-risk cohort. Pediatr Blood Cancer 2008;50:976–82. 37. Kager L, Zoubek A, Potschger U, et al. Primary metastatic osteosarcoma: presentation and outcome of patients treated on neoadjuvant Cooperative Osteo- sarcoma Study Group protocols. J Clin Oncol 2003;21(10):2011–8. 38. Harris MB, Gieser P, Goorin AM, et al. Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. J Clin Oncol 1998;16:3641–8. 39. Letourneau PA, Shackett B, Xiao L, et al. Resection of pulmonary metastases in pediatric patients with Ewing sarcoma improves survival. J Pediatr Surg 2011; 46(2):332–5. 40. Italiano A, Mir O, Cioffi A, et al. Advanced chondrosarcomas: role of chemotherapy and survival. Ann Oncol 2013;24(11):2916–22. 41. Eilber F, Giuliano A, Eckardt J, et al. Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 1987;5(1):21–6. 42. Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986;314(25):1600–6. 43. Goorin AM, Schwartzentruber DJ, Devidas M, et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J Clin Oncol 2003;21:1574–80. 44. Smith J, Heelan RT, Huvos AG, et al. Radiographic changes in primary osteogenic sarcoma following intensive chemotherapy: radiological-pathological correlation in 63 patients. Radiology 1982;143:355–60. 45. Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 2005;23:2004–11. 46. Bacci G, Bertoni F, Longhi A, et al. Neoadjuvant chemotherapy for high-grade central osteosarcoma of the extremity: histologic response to preoperative chemotherapy correlates with histologic subtype of the tumor. Cancer 2003; 97:3068–75. 1098 Gutowski et al

47. Walczak BE, Irwin RB. Sarcoma chemotherapy. J Am Acad Orthop Surg 2013; 21:480–91. 48. Bacci G, Ferrari S, Bertoni F, et al. Histologic response of high-grade nonmetastatic osteosarcoma of the extremity to chemotherapy. Clin Orthop Relat Res 2001;386:186–96. 49. Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the Instituto Ortopedico Rizzoli according to the Instituto Ortopedico Rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol 2000;18(24):4016–27. 50. Maki RG. Ifosfamide in the neoadjuvant treatment of osteogenic sarcoma. J Clin Oncol 2012;30(17):2033–5. 51. Bielack SS, Smeland S, Whelan JS, et al. Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial. J Clin Oncol 2015;33(20): 2279–87. 52. Bramwell VH, Burgers M, Sneath R, et al. A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup. J Clin Oncol 1992;10:1579. 53. Chawla SP, Sankhala KK, Chua V, et al. A phase II study of AP23573 (an mTOR inhibitor) in patients (pts) with advanced sarcomas (abstract). J Clin Oncol 2005;24:833s. 54. Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival: a report from the Chil- dren’s Oncology Group. J Clin Oncol 2008;26:633–8. 55. Arndt CA, Rose PS, Folpe AL, et al. Common musculoskeletal tumors of child- hood and adolescence. Mayo Clin Proc 2012;87(5):475–87. 56. Gibbs CP Jr, Weber K, Scarborough MT. Malignant bone tumors. Instr Course Lect 2002;51:413–28. 57. Ewing J. Diffuse endothelioma of bone. CA Cancer J Clin 1972;22:95–8. 58. Phillips RF, Higinbotham NL. The curability of Ewing’s endothelioma of bone in children. J Pediatr 1967;70:391–7. 59. Bacci G, Picci P, Gitelis S, et al. The treatment of localized Ewing’s sarcoma: the experience at the Instituto Rizzoli in 163 cases treated with and without adjuvant chemotherapy. Cancer 1982;49:1561–70. 60. Lee J, Hoang BH, Ziogas A, et al. Analysis of prognostic factors in Ewing sarcoma using a population-based cancer registry. Cancer 2010;116:1964–73. 61. Cotterill SJ, Ahrens S, Paulussen M, et al. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. J Clin Oncol 2000;18(17):3108–14. 62. Newbit ME, Gehan EA, Burgert EO, et al. Multimodal therapy for management of primary, nonmetastatic Ewing’s sarcoma of bone: a long-term follow-up for the First Intergroup study. J Clin Oncol 1990;8:1664–74. 63. Burgert EO, Nesbit ME, Garnsey LA, et al. Multimodal therapy for the management of nonpelvic, localized Ewing’s sarcoma of bone: intergroup Study IESS-II. J Clin Oncol 1990;8:1514–24. 64. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med 2003;348:694–701. Management of Bone Sarcoma 1099

65. Ferrari S, Sundby Hall K, Luksch R, et al. Nonmetastatic Ewing family tumors: high-dose chemotherapy with stem cell rescue in poor responder patients. Re- sults of the Italian Sarcoma Group/Scandinavian Sarcoma Group III protocol. Ann Oncol 2011;22:1221–7. 66. Granowetter L, Womer R, Devidas M, et al. Dose-intensified compared with standard chemotherapy for nonmetastatic Ewing sarcoma family of tumors: a Children’s Oncology Group Study. J Clin Oncol 2009;27:2536. 67. Womer RB, Daller RT, Fenton JG, et al. Granulocyte colony stimulating factor permits dose intensification by interval compression in the treatment of Ewing’s sarcomas and soft tissue sarcomas in children. Eur J Cancer 2000;36:87. 68. Womer RB, West DC, Krailo MD, et al. Randomized controlled trial of interval- compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children’s Oncology Group. J Clin Oncol 2012;30:4148. 69. Womer RB, West DC, Krailo MD, et al. Chemotherapy intensification by interval compression in localized Ewing sarcoma family of tumors (ESFT) (abstract 855). Data presented at the 13th annual meeting of the Connective Tissue Oncology Society (CTOS). Seattle, Washington, October 31-November 2, 2007. Abstract 855. Available at: http://www.ctos.org/meeting/2007/program.asp. Accessed December 11, 2012. 70. Oberlin O, Rey A, Desfachelles AS, et al. Impact of high-dose busulfan plus melphalan as consolidation in metastatic Ewing tumors: a study by the Socie´te´ Franc¸aise des Cancers de l’Enfant. J Clin Oncol 2006;24:3997. 71. Meyers PA, Krailo MD, Ladanyi M, et al. High-dose melphalan, etoposide, total- body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing’s sarcoma does not improve prognosis. J Clin Oncol 2001;19:2812. 72. Ladenstein R, Lasset C, Pinkerton R, et al. Impact of megatherapy in children with high-risk Ewing’s tumours in complete remission: a report from the EBMT Solid Tumour Registry. Bone Marrow Transplant 1995;15:697. 73. Juergens C, Weston C, Lewis I, et al. Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of Ewing tumors in the EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 2006;47:22. 74. Eriksson AI, Schiller A, Mankin JH. The management of chondrosarcoma of bone. Clin Orthop 1980;153:44–66. 75. Gelderblom H, Hogendoorn PCW, Dijkstra SD, et al. The clinical approach to- wards chondrosarcoma. Oncologist 2008;13:320–9. 76. Mitchell AD, Ayoub K, Mangham DC, et al. Experience in the treatment of dedifferentiated chondrosarcoma. J Bone Joint Surg Br 2000;82:55–61. 77. Staals EL, Bacchini P, Mercuri M, et al. Dedifferentiated chondrosarcoma arising in preexisting osteochondromas. J Bone Joint Surg Am 2007;89:987–93. 78. Grimer RJ, Gosheger G, Taminiau A, et al. Dedifferentiated chondrosarcoma: prognostic factors and outcome from a European group. Eur J Cancer 2007; 43(14):2060–5. 79. Dickey ID, Rose PS, Fucks B, et al. Dedifferentiated chondrosarcoma: the role of chemotherapy with updated outcomes. J Bone Joint Surg Am 2004;86(11): 2412–8. 80. Rohle D, Popvici-Muller J, Palaskas N, et al. An inhibitor of mutant IDH-1 delays growth and promotes differentiation in glioma cells. Science 2013;340:626–30. 1100 Gutowski et al

81. Lin C, McGough R, Aswad B, et al. Hypoxia induces HIF-1alpha and VEGF expression in chondrosarcoma cells and chondrocytes. J Orthop Res 2004; 22(6):1175–81. 82. Dallas J, Imanirad I, Rajani R, et al. Response to sunitinib in combination with proton beam radiation in a patient with chondrosarcoma: a case report. J Med Case Rep 2012;6:41. 83. Schrage YM, Lam S, Jochemsen AG, et al. Central chondrosarcoma progression is associated with pRb pathway alterations; CDK4 downregulation and p16 overexpression inhibit cell growth in vitro. J Cell Mol Med 2008;13(9A): 2843–52. 84. Bertino JR, Waud WR, Parker WB, et al. Targeting tumors that lack methylthioa- denosine phosphorylase (MTAP) activity: current strategies. Cancer Biol Ther 2011;11(7):627–32. 85. Van Oosterwijk JG, Anninga JK, Gelderblom H, et al. Update on targets and novel treatment options for high grade osteosarcoma and chondrosarcoma. Hematol Oncol Clin North Am 2013;27(5):1021–48. 86. Bernstein-Molho R, Kollender Y, Issakov J, et al. Clinical activity of mTOR inhibition in combination with cyclophosphamide in the treatment of recurrent unresectable chondrosarcomas. Cancer Chemother Pharmacol 2012;70:855. 87. DuBois SG, Krailo MD, Gebhardt MC, et al. Comparative evaluation of local control strategies in localized Ewing sarcoma of bone. Cancer 2015;121:467–75. 88. Schuck A, Ahrens S, Paulussen M, et al. Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys 2003;55:168–77. 89. Ozaki T, Hillmann A, Hoffmann C, et al. Significance of surgical margin on the prognosis of patients with Ewing’s sarcoma. A report from the Cooperative Ewing’s Sarcoma Study. Cancer 1996;78:892–900. 90. Bacci G, Longhi A, Briccoli A, et al. The role of surgical margins in the treatment of Ewing’s sarcoma family tumors: experience of a single institution with 512 patients treated with adjuvant and neoadjuvant chemotherapy. Int J Radiat Oncol Biol Phys 2006;65(3):766–72. 91. Baumann BC, Lustig RA, Mazzoni S, et al. A prospective clinical trial of proton therapy for chordoma and chondrosarcoma. Int J Radiat Oncol Biol Phys 2015; 93(3-S):E641. 92. Ozaki T, Hillmann A, Rube C, et al. The impact of intraoperative brachytherapy on surgery of Ewing’s sarcoma. J Cancer Res Clin Oncol 1997;123(1):53–6. 93. Sole CV, Calvo FA, Polo A, et al. Intraoperative electron-beam radiation therapy for pediatric Ewing sarcomas and rhabdomyosarcomas: long-term outcomes. Int J Radiat Oncol Biol Phys 2015;92(5):1069–76. 94. Rombi B, DeLaney TF, MacDonald SM, et al. Proton radiotherapy for pediatric Ewing’s sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys 2012; 82(3):1142–8. 95. Hoekstra HJ, Sindelar WF, Kinsella TJ. Surgery with intraoperative radiotherapy for sarcomas of the pelvic girdle: a pilot experience. Int J Radiat Oncol Biol Phys 1988;15:1013–6. 96. Weber DC, Badiyan S, Malyapa R, et al. Long-term outcomes of and prognostic factors of skull-base chondrosarcoma patients treated with pencil-beam scan- ning proton therapy at the Paul Scherrer Institute. Neuro Oncol 2015;18(2): 236–43. 97. Kamada T, Tsujii H, Tsuji H, et al. Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas. J Clin Oncol 2002;20:4466–71. Management of Bone Sarcoma 1101

98. Imai R, Kamada T, Araki N, Working Group for Bone and Soft Tissue Sarcomas. Carbon ion radiotherapy for unresectable sacral chordoma: an analysis of 188 cases. Int J Radiat Oncol Biol Phys 2016;95(1):322–7. 99. Sugahara S, Kamada T, Imai R, et al, Working Group for the Bone and Soft Tissue Sarcomas. Carbon ion radiotherapy for localized primary sarcoma of the extremities: results of a phase I/II trial. Radiother Oncol 2012;105(2):226–31. 100. Matsunobu A, Imai R, Kamada T, et al. Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk. Cancer 2012;118(18):4555–63. 101. Imai R, Kamada T, Sugahara S, et al. Carbon ion radiotherapy for sacral chordoma. Br J Radiol 2011;84(S-1):S48–54. 102. Ruggieri P, Angelini A, Ussia G, et al. Surgical margins and local control in resection of sacral chordomas. Clin Orthop Relat Res 2010;468(10):2939–47. 103. Hulen CA, Temple T, Fox WP, et al. Oncologic and functional outcome following sacrectomy for sacral chordoma. J Bone Joint Surg Am 2006;88(7):1532–9. 104. Nishida Y, Kamada T, Imai R, et al. Clinical outcome of sacral chordoma with carbon ion radiotherapy compared with surgery. Int J Radiat Oncol Biol Phys 2011; 79:110–6. 105. Berrington de Gonzalez A, Kutsenko A, Rajaraman P. Sarcoma risk after radiation exposure. Clin Sarcoma Res 2012;2(1):18. 106. Gladdy RA, Qin LX, Moraco N, et al. Do radiation-associated soft tissue sarcomas have the same prognosis as sporadic soft tissue sarcomas? J Clin Oncol 2010;28(12):2064–9. 107. Paulino AC. Late effects of radiotherapy for pediatric extremity sarcomas. Int J Radiat Oncol Biol Phys 2004;60(1):265–74. 108. Bacci G, Forni C, Longhi A, et al. Local recurrence and local control of nonmetastatic osteosarcoma of the extremities: a 27-year experience in a single institution. J Surg Oncol 2007;96:118–23. 109. Fiorenza F, Abudu A, Grimer RJ, et al. Risk factors for survival and local control in chondrosarcoma of bone. J Bone Joint Surg Br 2002;84:93–9. 110. Kawaguchi N, Ahmed AR, Matsumoto S, et al. The concept of curative margin in surgery for bone and soft tissue sarcoma. Clin Orthop Relat Res 2004;419: 165–72. 111. Ozaki T, Flege S, Liljenqvist U, et al. Osteosarcoma of the spine: experience of the Cooperative Osteosarcoma Study Group. Cancer 2002;94(4):1069. 112. Schoenfeld AJ, Hornicek FJ, Pedlow FX, et al. Osteosarcoma of the spine: experience in 26 patients treated at the Massachusetts General Hospital. Spine J 2010;10(8):708–14. 113. Farfalli GL, Albergo JI, Ritacco LE, et al. Oncologic and clinical outcomes in pelvic primary bone sarcomas treated with limb salvage surgery. Musculoskelet Surg 2015;99(3):237–42. 114. Grimer RJ. Surgical options for children with osteosarcoma. Lancet Oncol 2005; 6:85–92. 115. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb- sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982;196:305–15. 116. Bacci G, Ferrari S, Lari S, et al. Osteosarcoma of the limb: amputation or lib salvage in patients treated with neoadjuvant chemotherapy. J Bone Joint Surg Br 2002;84:88–92. 1102 Gutowski et al

117. Reddy KIA, Wafa H, Gaston CL, et al. Does amputation offer any survival benefit over limb salvage in osteosarcoma patients with poor chemonecrosis and close margins? Bone Joint J 2015;97-B:115–20. 118. Rougraff BT, Simon MA, Kneisl JS, et al. Limb salvage compared with amputation for osteosarcoma of the distal end of the femur: a long-term oncological, functional, and quality of life study. J Bone Joint Surg Am 1994;76:649–56. 119. Nagarajan R, Neglia JP, Clohisy DR, et al. Limb salvage and amputation in survivors of pediatric lower-extremity bone tumors: what are the long-term implications? J Clin Oncol 2002;20(22):4493. 120. Furtado S, Grimer RJ, Cool P, et al. Physical functioning, pain, and quality of life after amputation for musculoskeletal tumours. A national survey. Bone Joint J 2015;97-B:1284–90. 121. Malek F, Somerson JS, Mitchel S, et al. Does limb-salvage surgery offer patients better quality of life and functional capacity than amputation? Clin Orthop Relat Res 2012;470:2000–6. 122. Hobusch GM, Lang N, Schuh R, et al. Do patients with Ewing’s sarcoma continue with sports activities after limb salvage surgery of the lower extremity? Clin Orthop Relat Res 2015;473(3):839–46. 123. Mason GE, Aung L, Gall S, et al. Quality of life following amputation or limb preservation in patients with lower extremity bone sarcoma. Front Oncol 2013; 3(210):1–6. 124. Grimer RJ, Carter SR, Pynsent PB. The cost-effectiveness of limb salvage for bone tumors. J Bone Joint Surg Br 1997;79-B(4):558–61. 125. Renard AJ, Veth RP, Schreuder HWB, et al. Function and complications after ablative and limb-salvage therapy in lower extremity sarcoma of bone. J Surg Oncol 2000;73(4):198–205. 126. Henderson ER, O’Connor MI, Ruggieri P, et al. Classification of failure of limb salvage after reconstructive surgery for bone tumors. Bone Joint J 2014;96-B: 1436–40. 127. Grimer RJ, Chandrasekar CR, Carter SR, et al. Hindquarter amputation. Is it still needed and what are the outcomes? Bone Joint J 2013;95-B:127–31. 128. Bacci G, Picci P, Ferrari S, et al. Primary chemotherapy and delayed surgery for nonmetastatic osteosarcoma of the extremities: results in 164 patients preoperatively treated with high doses of methotrexate followed by cisplatin and doxorubicin. Cancer 1993;72:3227–38. 129. Nichter S, Menendez LR. Reconstructive considerations for limb salvage surgery. Orthop Clin North Am 1993;24:511–21. 130. Jeys LM, Grimer RJ, Carter SR, et al. Periprosthetic infection in patients treated for an orthopaedic oncological condition. J Bone Joint Surg Am 2005;87:842–9. 131. Angelini A, Drago G, Trovarelli G, et al. Infection after surgical resection for pelvic bone tumors: an analysis of 270 patients from one institution. Clin Orthop Re- lat Res 2014;472:349–59. 132. Aponte-Tinao LA, Ayerza MA, Muscolo DL, et al. What are the risk factors and management options for infection after reconstruction with massive bone allografts? Clin Orthop Relat Res 2016;474:669–73. 133. Brosojo O. Surgical procedure and local recurrence in 223 patients treated 1982-1997 according to two osteosarcoma chemotherapy protocols. The Scan- dinavian Sarcoma Group experience. Acta Orthop Scand Suppl 1999;285: 58–61. 134. Li X, Moretti VM, Ashana AO, et al. Impact of close surgical margin on local recurrence and survival in osteosarcoma. Int Orthop 2012;36:131–7. Management of Bone Sarcoma 1103

135. Andreou D, Bielack SS, Carrle D, et al. The influence of tumor- and treatment- related factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooper- ative Osteosarcoma Study Group protocols. Ann Oncol 2011;22(5):1228–35. 136. Grimer RJ, Sommerville S, Warnock D, et al. Management and outcome after local recurrence of osteosarcoma. Eur J Cancer 2005;41:578–83. 137. Rodriguez-Galindo C, Shah N, McCarville MB, et al. Outcome after local recurrence in osteosarcoma: the St. Jude Children’s Research Hospital experience (1970-2000). Cancer 2004;100:1928–35. 138. Weeden S, Grimer RJ, Cannon SR, et al. The effect of local recurrence on survival in resected osteosarcoma. Eur J Cancer 2001;37:39–46. 139. Kempf-Bielack B, Bielack SS, Jurgens H, et al. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Coopera- tive Osteosarcoma Study Group (COSS). J Clin Oncol 2005;23:559–68. 140. Grimer RJ, Taminiau AM, Cannon SR. Surgical subcommittee of the European Osteosarcoma Intergroup. Surgical outcomes in osteosarcoma. J Bone Joint Surg Br 2002;84:395–400. 141. Takeuchi A, Lewis VO, Satcher RL, et al. What are the factors that affect survival and relapse after local recurrence of osteosarcoma? Clin Orthop Relat Res 2014;472(1):3188–95. 142. Kong CB, Song WS, Cho WH, et al. Local recurrence has only small effect on survival in high-risk extremity osteosarcoma. Clin Orthop Relat Res 2012; 470(5):1482–90. 143. Bacci G, Longhi A, Cesari M, et al. Influence of local recurrence on survival in patients with extremity osteosarcoma treated with neoadjuvant chemotherapy: the experience of a single institution with 44 patients. Cancer 2006;106:2701–6. 144. Loh AHP, Navid F, Wang C, et al. Management of local recurrence of pediatric osteosarcoma following limb-sparing surgery. Ann Surg Oncol 2014;21: 1948–55. 145. Fox EJ, Anwar M, Gebhardt MC, et al. Long-term followup of proximal femoral allografts. Clin Orthop Relat Res 2002;397:106–13. 146. Bus MPA, Dijkstra PDS, van de Sande MA, et al. Intercalary allograft reconstructions following resection of primary bone tumors. J Bone Joint Surg Am 2014; 19(96):e26. 147. Sorger JI, Hornicek FJ, Zavatta M, et al. Allograft fractures revisited. Clin Orthop Relat Res 2001;382:66–74. 148. Mankin HJ, Springfield DS, Gebhardt MC, et al. Current status of allografting for bone tumors. Orthopedics 1992;15:1147–54. 149. Aponte-Tinao L, Ayerza MA, Muscolo DL, et al. Survival, recurrence, and function after epiphyseal preservation and allograft reconstruction in osteosarcoma of the knee. Clin Orthop Relat Res 2015;473:1789–96. 150. Aponte-Tinao L, Farfalli GL, Ritacco LE, et al. Intercalary femur allografts are an acceptable alternative after tumor resection. Clin Orthop Relat Res 2012;470(3): 728–34. 151. Ortiz-Cruz E, Gebhardt MC, Jennings LC, et al. The results of transplantation of intercalary allografts after resection of tumors. A long-term follow-up study. J Bone Joint Surg Am 1997;79(1):97–106. 152. Frisoni T, Cevolani L, Giorgini A, et al. Factors affecting outcome of massive intercalary bone allografts in the treatment of tumours of the femur. J Bone Joint Surg Br 2012;94(6):836–41. 1104 Gutowski et al

153. Berrey BH Jr, Lord CF, Gebhardt MC, et al. Fractures of allografts. Frequency, treatment, and end results. J Bone Joint Surg Am 1990;72:825–33. 154. Houdek MT, Wagner ER, Stans AA, et al. What is the outcome of allograft and intramedullary free fibula (Capanna Technique) in pediatric and adolescent patients with bone tumors? Clin Orthop Relat Res 2016;474:660–8. 155. Capanna RB, Campanacci M. A new technique for reconstructions of large metadiaphyseal bone defects. Orthop Traumatol 1993;3:159–77. 156. Capanna R, Campanacci DA, Belot N, et al. A new reconstructive technique for intercalary defects of long bones: the association of massive allograft with vascularized fibular autograft. Long-term results and comparison with alternative techniques. Orthop Clin North Am 2007;38:51–60. 157. Enneking WF, Campanacci DA. Retrieved human allografts. A clinicopatholog- ical study. J Bone Joint Surg Am 2001;83A:971–86. 158. Aponte-Tinao LA, Ritacco LE, Albergo JI, et al. The principles and applications of fresh frozen allografts to bone and joint reconstruction. Orthop Clin North Am 2014;45(2):257–69. 159. Gitelis S, Rasecki P. Allograft prosthetic composite arthroplasty for osteosarcoma and other aggressive bone tumors. Clin Orthop Relat Res 1991;270:197–201. 160. Farid Y, Lin PP, Lewis VO, et al. Endoprosthetic and allograft-prosthetic composite reconstruction of the proximal femur for bone neoplasms. Clin Orthop Relat Res 2006;442:223–9. 161. Benedetti MG, Bonatti E, Malfitano C, et al. Comparison of allograft-prosthetic composite reconstruction and modular prosthetic replacement in proximal femur bone tumors: functional assessment by gait analysis in 20 patients. Acta Orthop 2013;84(2):218–23. 162. Gitelis S, Heligman D, Quill G, et al. The use of large allografts for tumor reconstruction and salvage of the failed total hip arthroplasty. Clin Orthop 1988;231:62. 163. King JJ, Nystrom LM, Grimer NB, et al. Allograft-prosthetic composite reverse total shoulder arthroplasty for reconstruction of proximal humerus tumor resections. J Shoulder Elbow Surg 2016;25:45–54. 164. Hejna MJ, Gitelis S. Allograft prosthetic composite replacement for bone tumors. Semin Surg Oncol 1997;13:18–24. 165. Racano A, Pazionis T, Farrokhyar F, et al. High infection rate outcomes in long- bone tumor surgery with endoprosthetic reconstruction in adults: a systematic review. Clin Orthop Relat Res 2013;471:2017–27. 166. Horowitz SM, Glasser DB, Lane JM, et al. Prosthetic and extremity survivorship after limb salvage for sarcoma. How long do the reconstructions last? Clin Or- thop Relat Res 1993;293:280–6. 167. Ahlmann ER, Menendez LR, Kermani C, et al. Survivorship and clinical outcome of modular endoprosthetic reconstruction for neoplastic disease of the lower limb. J Bone Joint Surg Br 2006;88-B:790–5. 168. Houdek MT, Wagner ER, Wilke BK, et al. Long term outcomes of cemented endoprosthetic reconstruction for periarticular tumors of the distal femur. Knee 2016;23(1):167–72. 169. Jeys LM, Kulkarni A, Grimer RJ, et al. Endoprosthetic reconstruction for the treatment of musculoskeletal tumors of the appendicular skeleton and pelvis. J Bone Joint Surg Am 2008;90:1265–71. 170. AlGheshyan F, Eltoukhy M, Zakaria K, et al. Comparison of gait parameters in distal femoral replacement using a metallic endoprosthesis versus allograft reconstruction. J Orthop 2015;12(S1):S25–30. Management of Bone Sarcoma 1105

171. Benedetti MG, Catani F, Donati D, et al. Muscle performance about the knee joint in patients who had distal femoral replacement after resection of a bone tumor. J Bone Joint Surg Am 2000;82(11):1619. 172. Spira E, Lubin E. Extracorporeal irradiation of bone tumors: a preliminary report. Isr J Med Sci 1968;4:1015–9. 173. Chen TH, Chen WM, Huang CK. Reconstruction after intercalary resection of malignant bone tumors: comparison between segmental allograft and extracorporeally-irradiated autograft. J Bone Joint Surg Br 2005;87-B:704–9. 174. Puri A, Gulia A, Jambhekar N, et al. The outcome of the treatment of diaphyseal primary bone sarcoma by resection, irradiation, and re-implantation of the host bone. J Bone Joint Surg Br 2012;94-B:982–8. 175. Cascio BM, Thomas KA, Wilson SC. A mechanical comparison and review of transverse, step-cut, and sigmoid osteotomies. Clin Orthop Relat Res 2003; 411:296–304. 176. Currey JD, Foreman J, Laketic I, et al. Effects of ionizing radiation on the mechanical properties of human bone. J Orthop Res 1997;15:111–7. 177. Krieg AH, Davidson AW, Stalley PD. Intercalary femoral reconstruction with extracorporeal irradiated autogenous bone graft in limb salvage surgery. J Bone Joint Surg Br 2007;89-B:366–71. 178. Zimel MN, Farfalli GL, Zindman AM, et al. Revision distal femoral arthroplasty with the Compress Ò prosthesis has low rate of mechanical failure at 10 years. Clin Orthop Relat Res 2016;474(2):528–36. 179. Cristofolini L, Bini S, Toni A. In vitro testing of a novel limb salvage prosthesis for the distal femur. Clin Biomech 1998;13:608–15. 180. Monument MJ, Bernthal NM, Bowles AJ, et al. What are the 5-year survivorship outcomes of compressive endoprosthetic osseointegration fixation of the femur? Clin Orthop Relat Res 2015;473:883–90. 181. Healey JH, Morris CD, Athanasian EA, et al. Compress knee arthroplasty has 80% 10-year survivorship and novel forms of bone failure. Clin Orthop Relat Res 2013;471:774–83. 182. Pedtke AC, Wustrack RL, Fang AS, et al. Aseptic failure: how does the CompressÒ implant compare to cemented stems? Clin Orthop Relat Res 2012;470:735–42. 183. Farfalli GL, Boland PJ, Morris CD, et al. Early equivalence of uncemented press- fit and compress femoral fixation. Clin Orthop Relat Res 2009;467:2792–9. 184. Bhangu AA, Kramer MJ, Grimer RJ, et al. Early distal femoral endoprosthetic survival: cemented stems versus the compress implant. Int Orthop 2006;30: 465–72. 185. Zimel MN, Hwang S, Riedel ER, et al. Carbon fiber intramedullary nails reduce artifact in postoperative advanced imaging. Skeletal Radiol 2015;44:1317–25. 186. Steinberg EL, Rath E, Shlaifer A, et al. Carbon fiber reinforced PEEK optima—a composite material biomechanical properties and wear/debris characteristic of CF-PEEK composites for orthopedic trauma implants. J Mech Behav Biomed Mater 2013;17:221–8. 187. Leung KS, Tang N, Cheung LWH, et al. Image-guided navigation in orthopaedic trauma. J Bone Joint Surg Br 2010;92-B:1332–7. 188. Jolles BM, Genoud P, Hoffmeyer P. Computer assisted cup placement techniques in total hip arthroplasty improves accuracy of placement. Clin Orthop Relat Res 2004;426:174–9. 189. Richter M, Cakir B, Schmidt R. Cervical pedicle screws: conventional versus computer-assisted placement of cannulated screws. Spine 2005;30:2280–7. 1106 Gutowski et al

190. Hufner T, Kfuri M Jr, Galanski M, et al. New indications for computer-assisted surgery: tumor resection in the pelvis. Clin Orthop Relat Res 2004;426:219–25. 191. Cartiaux O, Banse X, Paul L, et al. Computer-assisted planning and navigation improves cutting accuracy during simulated bone tumor surgery of the pelvis. Comput Aided Surg 2013;18:19–26. 192. Jeys L, Matharu GS, Nandra RS, et al. Can computer navigation-assisted surgery reduce the risk of an intralesional margin and reduce the rate of local recurrence in patients with a tumour of the pelvis or sacrum? Bone Joint J 2013; 95-B(10):1417–24. 193. Ritacco LE, Milano FE, Farfalli GL, et al. Accuracy of 3-D planning and navigation in bone tumor resection. Orthopedics 2013;36(7):e942–50. 194. Cho HS, Oh JH, Han I, et al. The outcomes of navigation-assisted bone tumour surgery: minimum three-year follow-up. J Bone Joint Surg Br 2012;94(10): 1414–20. 195. Muscolo DL, Ayerza MA, Aponte-Tinao LA, et al. Partial epiphyseal preservation and intercalary allograft reconstruction in high-grade metaphyseal osteosarcoma of the knee. J Bone Joint Surg Am 2004;86-A(12):2686–93. 196. Hinsche AF, Giannoudis PV, Smith RM. Fluoroscopy-based multiplanar image guidance for insertion of sacroiliac screws. Clin Orthop 2002;395:135–44. 197. Amiot LP, Lang K, Putzier M, et al. Comparative results between conventional and computer-assisted pedicle screw installation in the thoracic, lumbar, and sacral spine. Spine 2000;25(5):606–14. 198. Zura RD, Kahler DM. A transverse acetabular nonunion treated with computer- assisted percutaneous internal fixation: a case report. J Bone Joint Surg Am 2000;82A:219–24. 199. Wong KC, Kumta SM, Sze KY, et al. Use of a patient-specific CAD/CAM surgical jig in extremity bone tumor resection and custom prosthetic reconstruction. Comput Aided Surg 2012;17(6):284–93. 200. Docquier PL, Paul L, Cartiaux O, et al. Computer-assisted resection and reconstruction of pelvic tumor sarcoma. Sarcoma 2010;2010:125162.